1. Field of The Invention
The invention relates to the synthesis of hydroxy-.beta.-lactams with high enantiomeric purity and hydroxyamino acids derived therefrom.
The development of a process for the efficient production of hydroxy-.beta.-lactams and their derivatives with high enantiomeric purity in high yield is of great importance for the synthesis of biologically active compounds of medicinal interest. The hydroxy-.beta.-lactams with high enantiomeric purity can serve as precursors for the production of 2-hydroxy-3-amino acids (isoserines).
2. Background of Related Art
The hydroxyamino acids are an important class of amino acids, which include norstatine, statine, and their analogs. The structures of norstatine and statine are as follows: ##STR1##
These amino acids and their derivatives serve as important components of enzyme inhibitors for a variety of peptide-degrading enzymes (peptidases). Furthermore, hydroxy-.beta.-lactam with high enantiomeric purity can serve as a key intermediate in the semisynthesis of the important anti-tumor chemotherapeutic agent, taxol.
Norstatine, statine and their analogs have been used extensively as crucial amino acid residues in peptide-based inhibitors of such enzymes as renin and HIV protease. Structures of typical enzyme inhibitors of renin and HIV protease are shown below: ##STR2##
Renin inhibitors are very specific antihypertensive agents, and HIV protease inhibitors are expected to serve as key therapeutic agents for AIDS. Norstatine, statine and their analogs provide effective transition state mimics of the substrates for peptidases, which bind to the enzymes tightly and inhibit their actions. Those enzyme inhibitions are very sensitive to the enantiomeric purity of the hydroxyamino acid residues.
Taxol is a complex diterpene isolated from the bark of Taxus brevifolia (Pacific Yew). The structure of taxol is as follows: ##STR3##
Taxol possesses high cytotoxicity and strong antitumor activity and is currently in phase III clinical trials in the United States.
A more readily available taxol precursor can be isolated from the leaves of Taxus baccata. Extraction of fresh leaves yields 10-deacetyl baccatin III which has the following structure: ##STR4##
With the availability of 10-deacetyl baccatin III, taxol can be produced in a semi-synthetic fashion with the coupling of a side chain which is a N-benzoyl-(2R,3S)-3-phenylisoserine having the following structure: ##STR5##
Synthesis of the side chain via a Sharpless epoxidation in a process requiring eight steps has been described by Denis, J. N., et al., "An Efficient, Enantioselective Synthesis of the Taxol Side Chain", J. Org. Chem. 51, 46-50 (1986). The Denis et al. mode of synthesis of the taxol side chain is as follows:
Phenylacetylene is subject to 1) hydroxymethylation followed by 2) Lindlar reduction to yield cis-cinnamyl alcohol. ##STR6## 3) The cis-cinnamyl alcohol is subjected to the titanium-catalyzed epoxidation process to yield (2S,3R)-epoxy alcohol. ##STR7## 4) This epoxy alcohol is oxidized with RuCl.sub.3 and NaIO.sub.4, and 5) the reaction product converted to the methyl ester of the epoxide with ethereal diazomethane. 6) This methyl ester of the epoxide is transformed into the desired hydroxyazide by epoxide cleavage using azidotrimethylsilane and a catalytic amount of zinc chloride followed by acid hydrolysis. ##STR8## 7) The hydroxy azide is transformed into azido benzoate and hydrogenated in methanol to produce amino benzoate. 8) The amino benzoate is rearranged to give the product. ##STR9## Modifications in this method have also been described by Denis, J. N. et al., "An Improved Synthesis of the Taxol Side Chain and of RP56976", J. Org. Chem 55, 1957-1959 (1990).
U.S. Pat. No. 5,015,744 to Holton describes another process for preparing the side chain of taxol. In the Holton process, the starting materials are acyloxyacetyl chloride cyclocondensed with an imine derived from benzaldehyde and p-methoxyaniline. The reaction produces racemic hydroxy-.beta.-lactams which must be resolved into the pure enantiomers. After the optical resolution, the (3R,4S)-hydroxy-.beta.-lactam is reacted with ethyl vinyl ether and then converted to an oxazinone: ##STR10## The oxazinone is reacted with 7-O-triethylsilyl baccatin III to form the last precursor to taxol.
For antitumor activity of taxol, the side chain, N-benzoyl-(2R,3S)-3-phenylisoserine is crucial. This side chain must be highly enantiomerically pure.
Accordingly, it is an object of the invention to synthesize hydroxy-.beta.-lactams in high yield with high enantioselectivity, with a minimum of synthesis steps.
It is a further object of the invention to provide hydroxy-.beta.-lactams which act as precursors for a variety of biologically active compounds such as the side chain of taxol and its analogs and also norstatine, statine, their analogs, and other amino acid residues.